Asthma is a chronic inflammatory disease of the respiratory system in which the airways narrow in response to different stimuli such as exposure to allergens, cold air, exercise and others. This narrowing causes symptoms such as wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning.
Medication for asthma are used to reverse and prevent symptoms and airflow limitation and include controllers (or preventers) and relievers. The goal of treatment is to achieve “asthma control”, which means to minimize day- and night-time symptoms, activity limitation, airway narrowing and rescue bronchodilator use, and therefore reduce the risk of life-threatening exacerbations and long term morbidity.
Controllers are medications taken daily on a long-term basis that are useful in getting and keeping persistent asthma under control. Controllers include inhaled glucocorticoids, leukotriene modifiers, mast cell stabilizers, anticholinergics and long-acting β2-agonists.
Relievers include short-acting, selective β2-adrenoreceptor agonists, such as salbutamol and terbutaline, that act to relieve bronchoconstriction and its accompanying acute symptoms.
Chronic Obstructive Pulmonary Disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles, most often related to cigarette smoking.
The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema).
Chronic inflammation causes remodelling and narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory processes, leads to the loss of alveolar attachments to the small airways and decreases lung elastic recoil; in turn, these changes diminish the ability of the airways to remain open during expiration. The terms “emphysema” and “chronic bronchitis” are frequently used clinically and included in the definition of COPD. Emphysema, or destruction of the gas-exchanging surfaces of the lung (alveoli), describes one of several structural abnormalities present in patients with COPD.
As anticipated above, COPD is delineated by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The intensity as well as the cellular and molecular characteristics of the inflammation vary as the disease progresses. Over time, inflammation damages the lungs and leads to the pathologic changes characteristic of COPD (Sutherland et al.; N. Engl. J. Med. 2004 (350), 2689-97). In fact, COPD is characterised by an increase in neutrophils, macrophages, and T lymphocytes in various parts of the lungs. There may also be an increase of eosinophils in some patients, particularly during exacerbations.
Pharmacological therapy is used to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. Therefore, treatment of COPD heavily depends on anti-inflammatory and bronchodilator drugs. However, none of the existing medications for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease.
Andolast (CR 2039), chemically defined as N-4-(5-tetrazolyl)-phenyl-4-(5-tetrazolyl)-benzamide is a novel antiallergic and anti-inflammatory agent, belonging to a new class of calcium-activated potassium (K+) channel openers.
Different sets of experiments have shown that Andolast relieves the different components of the airways inflammatory response. The compound decreases both the antibody-mediated and the cell-mediated inflammatory responses in atopic subjects. With regard to the former, Andolast has a potent inhibitory effect on IL-4 dependent IgE synthesis by human B lymphocytes from allergic donors: this effect leads to the decrease in allergen-triggered mast cells sensitisation and consequently to the inhibition of IgE-dependent mediator release.
With respect to cell-mediated processes, preliminary in-vivo data from atopic asthmatic patients indicated that Andolast induces an inhibitory effect on T lymphocytes (Th2) production of the eosinophil recruiter cytokine IL-5.
The currently clinical pharmacology evidence indicates that Andolast administered by inhalation at doses ranging from 2 to 20 mg prevents in a dose-dependent fashion the airway hyperresponsiveness to specific as well as to non-specific bronchostimulation challenges such as AMP, exercise, UNDW (ultrasonically nebulized distilled water) and CAH (cold-dry air hyperventilation) in mild-moderate asthmatic patients. Moreover, Andolast completely prevents the early as well as the late airway response following specific antigen challenge.